Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: Phase I/II experience

Purpose: We have completed a phase I study, followed by three phase I/II st udies, in patients with metastatic melanoma, renal cell carcinoma (RCC), an d sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containin g a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/diol eyl-phosphatidyl-ethanol-amine (DMRIE/DOPE) and administered intratumorally . Patients and Methods: Twenty-four patients were treated in the phase I stud y Leuvectin doses were 10 mu g, 30 mu g, or 300 mu g weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melan oma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 mu g twice a week for 3 weeks, 750 mu g weekly for 6 weeks, and 1,500 mu g weekly for 6 weeks. Results: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional sym ptoms after treatment. In the phase I/II studies, 45 patients were assessab le for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two p atients with RCC and one with melanoma have achieved partial responses last ing from 16 to 19 months and continuing. In addition, two RCC, three melano ma, and six sarcoma patients had stable disease lasting from 3 ta 18 months and continuing. The plasmid was detected by polymerase chain reaction assa y in the posttreatment samples of 29 of 46 evaluated patients. Immunohistoc hemistry studies on serial biopsy specimens showed increased IL-2 expressio n and CD8(+) infiltration after treatment in the tumor samples of several p atients (12 and 16, respectively). Conclusion: Direct intratumoral injection of Leuvectin is a safe and possib ly effective immunotherapeutic approach in the treatment of certain tumor t ypes. (C) 1999 by American Society of Clinical Oncology.